Striatum plays an important role in reward-motivated learning such as that associated with habitual use of drugs of abuse or affective disorders. Furthermore, medium spiny neurons in striatum account for the highest expression of 5-HT6 receptors in brain. We have found that locally increased expression of 5-HT6 receptors in rat dorsal striatum using a viral vector impairs learning in a simple operant task using sucrose rewards. This is entirely reversed by a selective 5-HT6 antagonist, suggesting that increased 5-HT6 receptor activity was responsible for the impairment. However, the mechanism of how 5- HT6 receptors modulate striatal function and stimulus-response learning is not known. Therefore, we propose to examine the role of this receptor in striatal function. In the first Aim we will determine whether GABAergic or cholinergic interneurons express 5-HT6 receptors and we will determine the effects of chronic 5-HT6 agonist and antagonist treatments on gene expression in dorsal striatum. We will map changes in cellular activation using immediate early gene expression in animals that overexpress 5-HT6 receptors in dorsomedial striatum. In the second Aim, we will develop viral vectors that express 5-HT6 receptors selectively in neurons of either the direct or indirect pathway; these vector tools will greatly increase our precision in determining how 5-HT6 receptors modulate reward-motivated learning; we will use these tools to investigate which pathways mediate the effects of 5-HT6 receptors on striatal learning. These aims will refine the cellular and mechanistic features of 5-HT6 receptor effects in striatum, so that future studies can focus on the most salient aspects of 5-HT6 receptor regulation of motivated behavior. The ultimate goal of this project is to identify the functional consequences of 5-HT6 receptor manipulations in discrete neural circuits on important psychological processes that are relevant to addiction, cognitive function, and mood regulation; this may ultimately lead to novel therapies for these disorders.Projective Narrative [unreadable] [unreadable] Habit learning is a normal process that depends upon the dorsal striatum that can be subverted in addiction so that compulsive, habitual behaviors persist despite substantial negative consequences. This project is designed to identify the role of striatal 5-HT6 serotonin receptors in reward motivated learning using rat behavioral models, state of the art viral gene transfer strategies, and measurement of gene expression changes. The long-term goal is to identify a new and powerful target for medical treatment of addiction. [unreadable] [unreadable] [unreadable]